Significance/Aims. Obesity is characterized by increased body fat and propensity to numerous obesity-related illnesses, including hypertension, type II diabetes, cardiovascular, pulmonary and gallbladder disease, as well as some forms of cancer. The molecular basis of obesity in women is unknown. Obesity results from a positive energy balance. An individual may become obese with a "normal" rate of energy expenditure when intake is excessive, or with a "normal" level of food intake if energy expenditure is low. A low energy expenditure could be due to a metabolic defect or to hormonal abnormalities that are inherited. A novel polymorphism (TGGTrp --> CGGArg; codon 64) in the _3-adrenergic receptor gene was recently detected in a number of ethnic populations. The _3-adrenergic receptor is thought to play an important role in the regulation of energy expenditure and lipolysis. Subjects who harbor the polymorphism, tend to have a lower resting metabolic rate, higher body mass index and earlier onset of type II diabetes. Little is known, however, regarding the possible metabolic role of the _3-adrenergic receptor polymorphism as a contributor to low levels of energy expenditure that lead to obesity in older women. Our overall hypothesis is that the inherited polymorphism in the _3-adrenergic receptor gene contributes to the genetic basis of obesity via low levels of energy expenditure and fat metabolism in older women. Approach. Moderately obese women (50-65 y) who are homozygous or heterozygous for the _3-adrenergic receptor polymorphism will be weight-reduced, metabolically stabilized and compared to weight-reduced controls. We hypothesize that use of a post-obese model will unmask differences in energy expenditure that would otherwise be obscured by the obese state. Total daily energy expenditure, resting metabolic rate, the thermic effect of a meal, free-living physical activity, and fat metabolism will be compared among genotypes after weight reduction. These studies will help define the metabolic consequences of the _3-adrenergic receptor gene polymorphism in the regulation of daily energy expenditure and fat metabolism in older women. Progress in Reporting Period/Future Plans. Between 12/1/97 and 11/30/98 we have completed pre-weight loss testing on 37 women who are currently in weight loss. In addition, we have completed post-weight loss testing on 20 women. We have also published one manuscript from the pre-weight loss data. In the upcoming reporting period, we will introduce another 30 women into the study and complete post-weight loss testing on 20 to 40 women. At that point, we will have a large enough subject size with post-weight loss data to begin longitudinal analyses for manuscript preparation.